ABSTRACT Malaria is caused by the protozoan parasite, Plasmodium. It begins with the infection by Plasmodium sporozoites of the liver. This step is essential for the expansion of parasite numbers and the subsequent symptomatic erythrocytic cycle. Inhibition of pre-erythrocytic infection will prevent malaria pathology and relapses from P. vivax. Current drugs against pre-erythrocytic stages have significant side-effects or are expensive. Therefore, there is an urgent need for new drugs against pre-erythrocytic stages of Plasmodium. Our scientific premise is that inhibition of P. falciparum cGMP-dependent protein kinase (PfPKG) will block the pre-erythrocytic cycle, and impede the erythrocytic cycle. Our hypothesis is based on data demonstrating that (i) chemical inhibition of PfPKG prevents infection by P. falciparum sporozoites of tissue culture cells, and by P. berghei sporozoites of mice. (ii) Chemical or genetic inhibition of P. berghei PKG blocks development of invaded sporozoites into mature, infectious liver stages. We propose to initiate a medicinal chemistry effort to synthesize and test a new chemical series of PfPKG inhibitors. Validated hits from this series demonstrate in vitro selectivity for PfPKG, over its human homolog, in enzymatic activity assays and are activite against the parasite. We propose a medicinal chemistry effort to optimize molecules from this series to yield potent and PfPKG-selective compounds with whole-cell activity, acceptable pharmaceutical properties for in vivo testing in mice.